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Abstract
β-arrestin plays a key role in G protein-coupled receptor (GPCR) signaling and desensitization. Despite recent structural advances, the mechanisms that govern receptor-β-arrestin interactions at the plasma membrane of living cells remain elusive. Here, we combine single-molecule microscopy with molecular dynamics simulations to dissect the complex sequence of events involved in β-arrestin interactions with both receptors and the lipid bilayer. Unexpectedly, our results reveal that β-arrestin spontaneously inserts into the lipid bilayer and transiently interacts with receptors via lateral diffusion on the plasma membrane. Moreover, they indicate that, following receptor interaction, the plasma membrane stabilizes β-arrestin in a longer-lived, membrane-bound state, allowing it to diffuse to clathrin-coated pits separately from the activating receptor. These results expand our current understanding of β-arrestin function at the plasma membrane, revealing a critical role for β-arrestin preassociation with the lipid bilayer in facilitating its interactions with receptors and subsequent activation.
Original language | English |
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Pages (from-to) | 2238-2255.e20 |
Number of pages | 39 |
Journal | Cell |
Volume | 186 |
Issue number | 10 |
Early online date | 4 May 2023 |
DOIs | |
Publication status | Published - 11 May 2023 |
Keywords
- G protein-coupled receptors
- GPCR
- arrestin
- single-molecule microscopy
- TIRF
- protein-protein interactions
- plasma membrane
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